A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer

Phase 3Active Not RecruitingNCT04607421

Pfizer831 enrolled

Overview

The purpose of this study is to evaluate two study medicines (encorafenib plus cetuximab) taken alone or together with standard chemotherapy for the potential treatment of colorectal cancer that: * has spread to other parts of the body (metastatic); * has a certain type of abnormal gene called "BRAF"; and * has not received prior treatment. Participants in this study will receive one of the following study treatments: * Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic. * Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home. * Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home. This study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone. The study team will monitor how each participant responds to the study treatment for up to about 3 years.

The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. Since encorafenib has not previously been combined with chemotherapy, the tolerability and PK of EC in combination with mFOLFOX6 and in combination with FOLFIRI will be evaluated in separate cohorts in the safety lead-in portion of the trial in order to identify which chemotherapy combination is to be used in the Phase 3 portion of the study.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Interventions

EncorafenibDRUG

75 mg capsules

CetuximabDRUG

Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial

OxaliplatinDRUG

Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial

IrinotecanDRUG

Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial

LeucovorinDRUG

Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial

5-FUDRUG

Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial

CapecitabineDRUG

150 mg or 500 mg Tablet

BevacizumabDRUG

Optional Injection for intravenous use 100 mg/vial or 400 mg/vial

Eligibility

Sex: ALLMin age: 16 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Safety Lead-In = Male/female ≥ 18 years old * Phase 3 and Cohort 3: Male/female ≥ 16 years old (where permitted locally) * Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation * Prior systemic treatment in metastatic setting: 0-1 regimens for Safety Lead In; none for Phase 3 and Cohort 3. (Note: Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis \< 6 month from end of adj/neoadjuvant treatment ) * Measurable disease (Phase 3 and Cohort 3)/ Measurable or evaluable disease (Safety Lead-in) * ECOG PS 0-1 * Adequate organ function Exclusion Criteria: * Tumors that are locally confirmed or unknown MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition * Active bacterial or viral infections in 2 weeks prior to starting dosing * Symptomatic brain metastases

Locations (268)

Mayo Clinic Hospital

Phoenix, Arizona, United States

Mayo Clinic in Arizona - Scottsdale

Scottsdale, Arizona, United States

Keck Hospital of USC

Los Angeles, California, United States

LAC & USC Medical Center

Los Angeles, California, United States

USC / Norris Comprehensive Cancer Center

Los Angeles, California, United States

Outcomes

Primary Outcomes

Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs)

Incidence of dose limiting toxicity defined as any adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies occurring during the first 28 days of treatment

Time frame: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Phase 3: Progression free survival, by blinded independent review

Progression free survival, defined as the time from the date of randomization to the earliest documented disease progression or death due to any cause: encorafenib and cetuximab + mFOLFOX6 (Arm B) vs the Control Arm (Arm C)

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Objective response rate by blinded independent review

Objective response defined as complete response (CR), or partial response (PR) according to RECIST v1.1 based on BICR assessment, from the date of randomization until the date of the first documentation of progression of disease (PD)

Time frame: Duration of Phase 3, approximately 23 months

Cohort 3: Objective response rate by blinded independent review

Defined as CR, or PR according to RECIST v1.1 based on BICR assessment, from the date of randomization until the date of the first documentation of PD, death or start of new anticancer therapy

Time frame: Duration of Cohort 3, approximately 15 months.

Secondary Outcomes

Safety Lead-in: Incidence of adverse events

An adverse event is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship as assessed by CTCAE 4.03

Time frame: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Safety Lead-in: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms

Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion.

Time frame: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Safety Lead-in: Incidence of dose interruptions, dose modifications and discontinuations due to adverse events

Time frame: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Safety Lead-in: Overall response rate by investigator

Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v1.1: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI

Time frame: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Safety Lead-in: Duration of response by Investigator

Time frame: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Safety Lead-in:Progression free survival by Investigator

Progression free survival, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI

Time frame: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Safety Lead-in: Time to response by Investigator

Time to response, defined as the time from first dose to first radiographic evidence of response per RECIST v1.1: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI

Time frame: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Safety Lead-in: Overall survival

Overall survival defined as the time from the first dose to death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI

Time frame: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 36 months

Phase 3: Overall survival

Overall survival, defined as the time from the date of randomization to death due to any cause: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)

Time frame: Duration of Phase 3, approximately 50 months

Phase 3: Overall response rate by Investigator and by blinded independent review

Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v1.1: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Duration of response by Investigator and blinded independent review

Duration of response, defined as the time from the date of first radiographic evidence of response to the earliest documented disease progression per RECIST v1.1, or death due to any cause: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Time to response by blinded independent review and by Investigator

Time to response, defined as the time from first dose to first radiographic evidence of response per RECIST v1.1: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Progression free survival by Investigator and by blinded independent review

Progression free survival, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause:: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Progression free survival 2 by Investigator

Progression free survival 2, defined as the time from the date of randomization to the second objective disease progression per RECIST v1.1, or death from any cause, whichever occurs first: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Incidence of adverse events

An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 (Arm B)

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms

Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 (Arm B)

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)

EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire

The EQ-5D-5L is a standardized measure of health utility that provides a single index value for the participant's health status. It is frequently used for economic evaluations of health care and has been shown to be a valid and reliable instrument, and comprises a short descriptive system questionnaire and a visual analogue scale (EQ VAS) that are cognitively undemanding, taking about 2 minutes to complete

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Change from Baseline in the Patient Global Impression of Severity (PGIS)

The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires

The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change in symptoms or quality of life since starting treatment.

Time frame: Duration of Phase 3, approximately 36 months

Phase 3: Confirm the MSI-status in tumor tissue

Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue

Time frame: Once, pre-treatment

Phase 3: To determine the correlation between ctDNA levels, BRAF V600 alterations, and clinical outcome

ctDNA levels and BRAF V600 VAF from ctDNA analysis of plasma samples collected at baseline and on treatment

Time frame: Predose on Cycle 1 Day 1, 15, Cycle 2 Day 15, Cycle 7 Day 1 and EOT. Arm C sampling on Day 1 of Cycles 1-3, 9 and EOT. EOT is approx 36 months.

Safety Lead-in: Maximum plasma concentration of encorafenib, LHY746, irinotecan and SN-38

Time frame: Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days

Safety Lead-in: Area under the plasma concentration time curve of encorafenib, LHY746, irinotecan and SN-38

Safety Lead-in: Time to maximim plasma concentration time curve of encorafenib, LHY746, irinotecan and SN-38

Safety Lead-in: Maximum plasma concentration of encorafenib, LHY746 and oxaliplatin

Time frame: Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days

Safety Lead-in: Area under the plasma concentration time curve of encorafenib, LHY746 and oxaliplatin

Time frame: Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days

Safety Lead-in: Clearance of irinotecan, SN-38 and oxaliplatin

Changes in exposures of irinotecan and its metabolite (SN-38) on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 1 (encorafenib and cetuximab + FOLFIRI) Changes in exposures of oxaliplatin on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 2 (encorafenib and cetuximab + mFOLFOX6)

Safety Lead-in: Time to maximim plasma concentration time curve of encorafenib, LHY746 and oxaliplatin

Time frame: Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days

Phase 3: Trough concentrations of encorafenib and its metabolite LHY746

Trough plasma concentrations in all patients in Arm A and Arm B

Time frame: Predose on Cycle 1 through Cycle 6. Each cycle is 28 days

Cohort 3: Progression free survival by Investigator and by blinded independent review

Progression free survival, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause.

Time frame: Duration of Cohort 3, approximately 21 months

Cohort 3: Overall response rate by investigator

Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v 1.1

Time frame: Duration of Cohort 3, approximately 21 months

Cohort 3: Duration of response by Investigator and by blinded independent review

Duration of response, defined as the time from the date of first radiographic evidence of response to the earliest documented disease progression per RECIST v1.1, or death due to any cause

Time frame: Duration of Cohort 3, approximately 21 months

Cohort 3: Time to response by Investigator and by blinded independent review

Time to response, defined as the time from the date of randomization to first radiographic evidence of response per RECIST v1.1

Time frame: Duration of Cohort 3, approximately 21 months

Cohort 3: Overall survival

Overall survival, defined as the time from the date of randomization to death due to any cause

Time frame: Duration of Cohort 3, approximately 36 months

Cohort 3: Incidence of adverse events

Time frame: Duration of Cohort 3, approximately 21 months

Cohort 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms

Time frame: Duration of Cohort 3, approximately 21 months

Cohort 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)

Time frame: Duration of Cohort 3, approximately 21 months

Cohort 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire

Time frame: Duration of Cohort 3, approximately 21 months

Cohort 3: Change from Baseline in the Patient Global Impression of Severity (PGIS)

The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.

Time frame: Duration of Cohort 3, approximately 21 months

Cohort 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires

The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change in symptoms or quality of life since starting treatment.

Time frame: Duration of Cohort 3, approximately 21 months

Cohort 3: Confirm the MSI-status in tumor tissue

Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue

Time frame: Once, pre-treatment

Cohort 3: To determine the correlation between ctDNA levels, BRAF V600 alterations, and clinical outcome

ctDNA levels and BRAF V600 VAF from ctDNA analysis of plasma samples collected at baseline and on treatment

Time frame: Predose on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 15, Cycle 7 Day 1 and End of Treatment (Duration of Cohort 3, approximately 21 months). Each cycle is 28 days.

Cohort 3: Trough concentrations of encorafenib and its metabolite LHY746

Trough plasma concentrations in all patients in Arm D

Time frame: Predose on Cycle 1 through Cycle 6. Each cycle is 28 days

A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer

Overview

Conditions

Interventions

Eligibility

Locations (268)

Outcomes

Primary Outcomes

Secondary Outcomes